While treatment has greatly improved the condition of those with HIV infection, central nervous system dysfunction persists in a subset of HIV infected individuals. The proximal mechanism of neuronal damage, dysfunction, and death is not known. We have carried out analyses of many aspects of HIV (and the nonhuman primate SIV) induced damage to the brain. In this work, we discovered that a recently recognized system in acting in neuronal protection, known as autophagy, is inhibited in the HIV/SIV infected brain. We hypothesize this leads to enhanced susceptibility of neurons to damage and the resulting untoward consequences of brain dysfunction. Our long-term objective remains the same, to understand the mechanism leading to this dysfunction. In this renewal application we will focus on the role of alteration in neuronal autophagy in CNS damage resulting from HIV infection. This will be accomplished in three specific aims. First, molecules involved in the viral-host interaction in the brain that occurs in HIV infection will be assessed for effects on neuronal autophagy, using confocal imaging and molecular analysis. Second, we hypothesize that the inhibition of neuronal autophagy leads to the accumulation of specific proteins in neurons that can contribute to damage. These will be uncovered through quantitative proteomics and stringent validation. Third, we will relate these discoveries to the clinical condition by examining brain tissue molecularly and histopathologically for the presence of the molecules uncovered in the first two aspects. The study of neuronal autophagy will lead to a better understanding of the mechanisms of neuronal damage in HIV brain infection, as well as lead to ways to prevent or treat this condition. PUBLIC HEALTH RELEVANCE: While treatment for HIV infection has improved, infected individual still suffer the consequence of damage to targets for viral infection, including the brain. The way in which HIV injures the brain is not clear, and in the proposed experiments HIV-induced dysfunction of a prime protective pathway will be examined. Techniques to prevent or reverse this dysfunction could be useful in preventing or treating this devastating condition.